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Title page for ETD etd-11152018-125950

Type of Document Master's Thesis
Author Glass, Evan B.
URN etd-11152018-125950
Title Balancing Copper-Induced Cytotoxicity with Conjugation Efficiency in "Click" Chemistry of Polymeric Nanoparticles
Degree Master of Science
Department Biomedical Engineering
Advisory Committee
Advisor Name Title
Todd Giorgio Committee Chair
Fiona Yull Committee Member
  • polymeric nanoparticles
  • click chemistry
  • copper
  • macrophages
  • drug delivery
Date of Defense 2018-12-15
Availability restrictone
Advanced organic chemistry allows for design of unique nanocarriers that have specific functions tailored for in vivo applications, such as decorating with mannose to target tumor-associated macrophages for immunotherapy applications. One recent advancement that revolutionized polymer decoration was the development of the copper-catalyzed, alkyne-azide “click” reaction (CuAAC). CuAAC chemistry is a robust reaction that allows for functionalization of polymers with a high degree of controllability, but is associated with residual copper that can lead to cell toxicity. This study aimed to minimize the effects of copper-associated toxicity while maintaining “click” reaction conjugation efficiency by altering the amount of copper catalyst used in the CuAAC reaction. We tested the CuAAC reaction using a range of 0.1-1 mM copper catalyst and successfully reduced the amount of residual copper in our polymers while also maintaining conjugation efficiency near that of the standard 1 mM copper catalyst. We also demonstrated a reduction in cell toxicity by reducing residual copper, but surprisingly, we also discovered toxicity associated with the lowest catalyst concentration (0.1 mM). We hypothesize this toxicity was due to residual, unreacted azides. These polymers were then used to fabricate micellar complexes loaded with fluorescent markers to examine targeted uptake in polarized M2 macrophages. Overall, the polymer decorated using 0.75 mM copper catalyst exhibited the least toxicity and highest degree of specificity for uptake into M2 macrophages. These results indicate that copper-associated toxicity from the CuAAC reaction can be mitigated by altering catalyst concentration but still allow for effective conjugation.
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